The present invention relates to small molecule compounds that are able to modulate the biological activity of retinoid X receptors, and to methods for the production and therapeutic use of such compounds.
The vitamin A metabolite, retinoic acid, has long been recognized to induce a broad spectrum of biological effects. For example, retinoic acid-containing products, such as Retin-A(copyright) and Accutane(copyright), have found utility as therapeutic agents for the treatment of various pathological conditions. In addition, a variety of structural analogues of retinoic acid have been synthesized that also have been found to be bioactive. Many of these synthetic retinoids have been found to mimic many of the pharmacological actions of retinoic acid, and thus have therapeutic potential for the treatment of numerous disease states.
Medical professionals have become very interested in the therapeutic applications of retinoids. Among their uses approved by the FDA is the treatment of severe forms of acne and psoriasis as well as cancers such as Kaposi""s Sarcoma. A large body of evidence also exists that these compounds can be used to arrest and, to an extent, reverse the effects of skin damage arising from prolonged exposure to the sun. Other evidence exists that these compounds have clear effects on cellular proliferation, differentiation and programmed cell death (apoptosis), and thus, may be useful in the treatment and prevention of a variety of cancerous and pre-cancerous conditions, such as acute promyleocytic leukemia (APL), epithelial cancers, squamous cell carcinomas, including cervical and skin cancers and renal cell carcinoma. Furthermore, retinoids may have beneficial activity in treating and preventing diseases of the eye, cardiovascular disease and skin disorders.
Major insight into the molecular mechanism of retinoic acid signal transduction was gained in 1988, when a member of the steroid/thyroid hormone intracellular receptor superfamily was shown to transduce a retinoic acid signal. V. Giguere et al., Nature, 330:624-29 (1987); M. Petkovich et al., Nature, 330: 444-50 (1987); for a review, see R. M. Evans, Science, 240:889-95 (1988). It is now known that retinoids regulate the activity of two distinct intracellular receptor subfamilies: the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs), including their subtypes, RARxcex1,xcex2,xcex3 and RXRxcex1,xcex2,xcex3. All-trans-retinoic acid (ATRA) is an endogenous low-molecular-weight ligand that modulates the transcriptional activity of the RARs, while 9-cis retinoic acid (9-cis) is the endogenous ligand for the RXRs. R. A. Heyman et al., Cell, 68:397-406 (1992); and A. A. Levin et al., Nature, 355:359-61 (1992).
Although both the RARs and RXRs respond to ATRA in vivo, due to the in vivo conversion of some of the ATRA to 9-cis, the receptors differ in several important aspects. First, the RARs and RXRs are significantly divergent in primary structure (e.g., the ligand binding domains of RARxcex1 and RXRxcex1 have only approximately 30% amino acid homology). These structural differences are reflected in the different relative degrees of responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RARs and RXRs. For example, RXRxcex1 mRNA is expressed at high levels in the visceral tissues, e.g., liver, kidney, lung, muscle and intestine, while RARxcex1 mRNA is not. Finally, the RARs and RXRs have different target gene specificity. In this regard, RARs and RXRs regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of the consensus sequence AGGTCA. RAR:RXR heterodimers activate transcription ligand by binding to direct repeats spaced by five base pairs (a DR5) or by two base pairs (a DR2). However, RXR:RXR homodimers bind to a direct repeat with a spacing of one nucleotide (a DR1). D. J. Mangelsdorf et al., xe2x80x9cThe Retinoid Receptorsxe2x80x9d in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D. S. Goodman, Eds., Raven Press, New York, N.Y., 2nd Edition (1994). For example, response elements have been identified in the cellular retinal binding protein type II (CRBPII), which consists of a DR1, and in Apolipoprotein AI genes that confer responsiveness to RXR, but not to RAR. Further, RAR has also been shown to repress RXR-mediated activation through the CRBPII RXR response element (D. J. Manglesdorf et al., Cell, 66:555-61 (1991)). Also, RAR specific target genes have been identified, including target genes specific for RARxcex2 (e.g., xcex2RE), that consist of a DR5. These data indicate that two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay.
RXR agonists in the context of an RXR:RXR homodimer display unique transcriptional activity in contrast to the activity of the same compounds through an RXR heterodimer. Activation of a RXR homodimer is a ligand dependent event, i.e., the RXR agonist must be present to bring about the activation of the RXR homodimer. In contrast, RXR working through a heterodimer (e.g., RXR:RAR, RXR:VDR) is often the silent partner, i.e., no RXR agonist will activate the RXR-containing heterodimer without the corresponding ligand for the heterodimeric partner. However, for other heterodimers, (e.g., PPAR:RXR) a ligand for either or both of the heterodimer partners can activate the heterodimeric complex. Furthermore, in some instances, the presence of both an RXR agonist and the agonist for the other heterodimeric partner (e.g., gemfibrizol for PPARxcex1 and TTNPB for RARxcex1) leads to at least an additive, and often a synergistic enhancement of the activation pathway of the other IR of the heterodimer pair (e.g., the PPARxcex1 pathway). See e.g., WO 94/15902, published Jul. 21, 1994; R. Mukherjee et al., J. Steroid Biochem. Molec. Biol., 51:157-166 (1994); and L. Jow and R. Mukherjee, J. Biol. Chem., 270:3836-40 (1995).
RAR and RXR retinoid agonists, including both RAR specific and RXR specific agonists have been previously identified. See e.g., WO 94/15902, WO 93/21146, WO 94/15901, WO 94/12880, WO 94/17796, WO 94/20093, WO 96/05165 and Application No. PCT/US93/10166; EPO Patent Application Nos. 87110303.2, 87309681.2 and EP 0718285; U.S. Pat. Nos. 4,193,931, 4,539,134, 4,801,733, 4,831,052, 4,833,240, 4,874,747, 4,879,284, 4,898,864, 4,925,979, 5,004,730, 5,124, 473, 5,198,567, 5,391,569 and Re 33,533; and H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 2. Structure-Activity Relationship of Chalcone-4-carboxylic Acids and Flavone-4xe2x80x2-carboxylic Acidsxe2x80x9d, J. Med. Chem., 32:834 (1989); H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 3. Structure-Activity Relationships of Retinoidal Azobenzene-4-carboxylic Acids and Stilbene-4-carboxylic Acidsxe2x80x9d, J. Med. Chem., 32:1098 (1989); H. Kagechika et al., xe2x80x9cRetinobenzoic Acids. 4. Conformation of Aromatic Amides with Retinoidal Activity. Importance of trans-Amide Structure for the Activityxe2x80x9d, J. Med. Chem., 32:2292 (1989); M. Boehm et al., J. Med. Chem., 37:2930 (1994); M. Boehm et al., J. Med. Chem., 38:3146 (1995); E. Allegretto et al., Journal of Biol. Chem., 270:23906 (1995); R. Bissonnette et al., Mol. and Cellular Bio., 15:5576 (1995); R. Beard et al., J. Med. Chem., 38:2820 (1995); and M. I. Dawson et al., xe2x80x9cEffect of Structural Modifications in the C7-C11 Region of the Retinoid Skeleton on Biological Activity in a Series of Aromatic Retinoidsxe2x80x9d, J. Med. Chem., 32:1504 (1989).
Further, antagonists to the RAR subfamily of receptors have been identified. See e.g., C. Apfel et al., Proc. Natl. Acad. Sci., 89:7129 (1992); S. Keidel et al., Mol. Cell. Biol., 14:287 (1994); S. Kaneko et al., Med. Chem. Res., 1:220 (1991); L. Eyrolles et al., Med. Chem. Res., 2:361 (1992); J. Eyrolles et al., J. Med. Chem., 37:1508 (1994); M-O Lee et al., Proc. Natl. Acad. Sci., 91:5632 (1994); Yoshimura et al., J. Med. Chem., 38:3163 (1995); and U.S. Pat. No. 5,391,766. In addition, various polyene compounds have been disclosed to be useful in the treatment of inflammatory conditions, psoriasis, allergic reactions, and for use in sunscreens in cosmetic preparations. See e.g., U.S. Pat. Nos. 4,534,979 and 5,320,833. Also, trienediolates of hexadienoic acids have proved useful in the synthesis of retinoic and nor-retinoic acids. See M. J. Aurell, et al., Tetrahedron, 49:6089 (1993).
Compounds have also been found that are RXR antagonist (e.g., that bind to RXR and do not activate, but antagonize transcription) and/or RXR selective compounds that have distinct heterodimer selective properties, such that they are capable of manifesting agonist, partial agonist and antagonist properties. See WO 97/12853, published Apr. 10, 1997. RXR agonists compounds which have been identified so far have exhibited significant therapeutic utility, but they have also exhibited some undesirable side effects, such as elevation of triglycerides and suppression of the thyroid hormone axis (see, e.g., Sherman, S. I. et al., N. Engl. J. Med. 340(14):1075-1079 (1999).
The entire disclosures of the publications and references referenced to above and hereafter in this specification are incorporated herein by reference.
The present invention provides a novel class of RXR modulator compounds having the structure: 
wherein
R1 is selected from the group of hydrogen, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R2 and R4 are independently selected from the group of hydrogen, NR10R11, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, heteroaryl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be optionally substituted;
R3 is selected from the group of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, heteroaryl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be optionally substituted;
R5 and R6 are independently selected from the group of hydrogen, F, Cl, Br, I, CN, NH2, OH, SH, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, and aryloxy wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups may be optionally substituted; or
R5 and R6 taken together form a three- to eight-membered carbocyclic ring, a three- to eight-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein said carbocyclic ring, heterocyclic ring, aryl and heteroaryl groups may be optionally substituted;
R7 is selected from the group of C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 haloalkyl, wherein said alkyl, alkenyl, and haloalkyl groups may be optionally substituted;
R8 is selected from the group of hydrogen, F, Cl, Br, I, CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups may be optionally substituted;
R9 is selected from the group of hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R10 and R11 each independently is hydrogen or optionally substituted C1-C6 alkyl; or
R10 and R11 taken together with nitrogen form an optionally substituted five- or six-membered heterocyclic ring;
Y is selected from the group of NR12; O and S;
R12 is selected from the group of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 haloalkyl; and
pharmaceutically acceptable salts thereof.
Compounds of the present invention exhibit an improved pharmacologic profile relative to the profile of previously studied RXR modulators, including those that share common structural features with the presently disclosed modulator compounds. The present invention also provides synthetic methods for preparing these compounds as well as pharmaceutical compositions incorporating these novel compounds and methods for the therapeutic use of such compounds and pharmaceutical compositions.
These and various other advantages and features of novelty that characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying descriptive matter, in which there is described preferred embodiments of the invention.
The present invention is based on the discovery of a group of compounds that modulate the activity of the RXR receptor and unexpectedly exhibit a significantly improved pharmacologic profile. This new group of compounds does not exhibit the undesirable side effects of substantially raising triglyceride levels and substantially suppressing thyroid hormone axis, which have been associated with previously characterized RXR modulators.
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term xe2x80x9calkylxe2x80x9d, alone or in combination, refers to a straight-chain or branched-chain alkyl radical having from 1 to about 10 carbon atoms. Examples of alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 10 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.
The term xe2x80x9carylxe2x80x9d, alone or in combination, refers to an optionally substituted aromatic ring. The term aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring systems. The polyaromatic and polycyclic rings systems may contain from two to four, more preferably two to three, and most preferably two rings. Preferred aryl groups include five or six-membered aromatic ring systems. Examples of aryl groups include, without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems. Preferably the aryl groups of the present invention contain from five to about twenty carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, refers to an alkyl ether radical wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9caryloxyxe2x80x9d, alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benyloxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, refers to an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
The terms alkyl, alkenyl and alkynyl include straight-chain, branched-chain, saturated and/or unsaturated structures, and combinations thereof.
The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl, alkenyl and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms cycloalkyl and cycloalkene include optionally substituted, saturated and/or unsaturated C3-C7 carbocyclic structures.
The terms cycloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl include optionally substituted cycloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups.
The term carbocycle includes optionally substituted, saturated and/or unsaturated, three- to seven-membered cyclic structures in which all of the skeletal atoms are carbon.
The term heterocycle includes optionally substituted, saturated and/or unsaturated, three- to seven-membered cyclic structures in which one or more skeletal atoms is oxygen, nitrogen, sulfur, or combinations thereof.
The term xe2x80x9cheteroarylxe2x80x9d refers to optionally substituted aromatic ring systems having one or more heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems, and polyheteroaromatic ring systems where the ring system has from two to four, more preferably two to three, and most preferably two, rings. The terms heterocyclic, polycyclic heteroaromatic, and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems from two to four, more preferably two to three, and most preferably two, rings. The term heteroaryl includes ring systems such as, for example, pyridine, quinoline, furan, thiophene, pyrrole, pyrrolidine, piperidine, indole, imidazole, thiazole, benzthiazole, triazole and pyrazole. Preferably the heteroaryl groups of the present invention contain from about five to about 20 skeletal ring atoms.
The term acyl includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituents attached to a compound via a carbonyl functionality (e.g., xe2x80x94CO-alkyl, xe2x80x94CO-aryl, xe2x80x94CO-arylalkyl or heteroarylalkyl etc. . . . ).
The substituents of an xe2x80x9coptionally substitutedxe2x80x9d structure may include, without limitation, one or more , preferably one to four, and more preferably one to two of the following preferred substituents: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, cycloalkyl, arylalkyl, amino, alkylamino, dialkylamino, F, Cl, Br, I, CN, NO2, NH2, NHCH3, N(CH3)2, S, SH, SCH3, OH, OCH3, OCF3, CH3, CF3.
The term halogen refers to F, Cl, Br or I.
Protecting groups that may be used in the present invention include those that are commonly known to those skilled in the art, such groups include, but are not limited to, TBDMS, TBS, and BNZ.
RXR refers to RXRxcex1, RXRxcex2, RXRxcex3 and combinations thereof.
PPAR refers to PPARxcex1, PPARxcex2, PPARxcex31, PPARxcex32 and combinations thereof.
The term RXR modulator compound refers to a compound that binds to one or more Retinoid X Receptors and modulates (i.e., increases or decreases the transcriptional activity and/or biological properties of the given receptor dimer) the transcriptional activity of an RXR homodimer (i.e., RXR:RXR) and/or RXR in the context of a heterodimer, including but not limited to heterodimer formation with peroxisome proliferator activated receptors (e.g., RXR:PPARxcex1,xcex2,xcex31 or xcex32), thyroid receptors (e.g., RXR:TRxcex1 or xcex2), vitamin D receptors (e.g., RXR:VDR), retinoic acid receptors (e.g., RXR:RARxcex1,xcex2 or xcex3), NGFIB receptors (e.g., RXR:NGFIB), NURR1 receptors (e.g., RXR:NURR1) LXR receptors (e.g., RXR:LXRxcex1,xcex2), DAX receptors (e.g., RXR:DAX), as well as other orphan receptors that form heterodimers with RXR, as either an agonist, partial agonist and/or antagonist. The particular effect of an RXR modulator as an agonist, partial agonist and/or antagonist will depend upon the cellular context as well as the heterodimer partner in which the modulator compounds acts.
Compounds of the present invention that do not substantially raise triglyceride levels do not raise triglyceride levels by more than 50% in individuals having normal triglyceride plasma levels when such compounds are administered to such individuals in a pharmaceutically effective amount. Preferably, such compounds do not raise triglyceride levels by more than 25%. More preferably, such compounds do not raise triglyceride levels by more than 15%. Most preferably, such compounds decrease triglyceride levels when administered to such individuals in a pharmaceutically effective amount.
Compounds of the present invention that do not substantially suppress thyroid hormone axis do not decrease T4 levels in the blood by more than 50% in individuals having normal T4 levels when such compounds are administered to such individuals in a pharmaceutically effective amount. Preferably, such compounds do not decrease T4 levels in the blood by more than 25%. More preferably, such compounds do not decrease T4 levels in the blood by more than 15%. Most preferably, compounds of the present invention do not substantially increase or decrease T4 levels in the blood.
As used herein, the term disease includes, but is not limited to, syndrome X, NIDDM, diabetes, obesity, and cardiovascular disease.
As used herein, persons at risk for developing a disease condition are those who have one or more, preferably two or more risk factors for developing such a disease. Such risk factors include, but are not limited to, insulin resistance, obesity, hyperlipidemia, hypercholesterolemia, and hypertension.
In accordance with a first aspect of the present invention, we have developed compounds of the formulae: 
wherein
R1 is selected from the group of hydrogen, F, Cl, Br, I, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl, C2-C3 haloalkenyl, C2-C3 alkynyl, C2-C3 haloalkynyl, and C1-C3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R2 and R4 are independently selected from the group of hydrogen, NR10OR11, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, heteroaryl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be optionally substituted;
R3 is selected from the group of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, heteroaryl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be optionally substituted;
R5 and R6 are independently selected from the group of hydrogen, F, Cl, Br, I, CN, NH2, OH, SH, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, and aryloxy wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups may be optionally substituted; or
R5 and R6 taken together form a three- to eight-membered carbocyclic ring, a three- to eight-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein said carbocyclic ring, heterocyclic ring, aryl and heteroaryl groups may be optionally substituted;
R7 is selected from the group of C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 haloalkyl, wherein said alkyl, alkenyl, and haloalkyl groups may be optionally substituted;
R8 is selected from the group of hydrogen, F, Cl, Br, I, CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups may be optionally substituted;
R9 is selected from the group of hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R10 and R11 each independently is hydrogen or optionally substituted C1-C6 alkyl; or
R10 and R11 taken together with nitrogen form an optionally substituted five- or six-membered heterocyclic ring;
Y is selected from the group of NR12, O and S;
R12 is selected from the group of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 haloalkyl; and
pharmaceutically acceptable salts thereof.
In one embodiment, the present invention provides a method for preparing compounds of formula 1 using a coumarin intermediate. Such a method includes treating a coumarin intermediate of structural formula 4: 
with a reducing agent to form a diol of structural formula 7: 
wherein R1, R2, R3, R4, R5, and R6 are as previously defined. Preferably, such a method further includes the step of selectively alkylating the phenol oxygen of the diol of structural formula 7 with R7X in the presence of a base to form a primary allylic alcohol of structural formula 8: 
treating the allylic alcohol of structural formula 8 with an oxidant to form an aldehyde of structural formula 9: 
treating the aldehyde of structural formula 9 with a phosphonate of structural formula 10: 
to form an ester of formula 1-E: 
and hydrolyzing the ester, 1-E; wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as previously defined. Preferably, Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 each independently is methyl, ethyl or iso-propyl.
In another embodiment, the present invention provides a method for preparing compounds of formula 1, which includes the steps of treating alkoxyarylhalide 12
with a trialkyl borate and a base under Pd-catalysis to form a compound of structural formula 14
treating a compound of structural formula 14 with a compound of structural formula 15: 
to form a compound of structural formula 16: 
wherein A is COORxe2x80x2 or COPg, Pg is a protecting group, R and Rxe2x80x2 each is hydrogen or alkyl; Xa and Xb each independently is halogen; and R1, R2, R3, R4, R5, R6, and R7 are as previously defined. In this embodiment, it is preferred where R is hydrogen and Rxe2x80x2 is methyl or ethyl.
In yet another embodiment, the present invention provides a method for preparing compounds of formula 1, which includes the steps of treating a ketone of structural formula VI: 
with a phosphonate of structural formula 10b: 
wherein Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 each independently is alkyl or aryl and R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as previously defined. In this embodiment, it is preferred where R9 is halogen, most preferably F.
In still another embodiment, the present invention provides a method for preparing a compound of structural formula 1b: 
which includes the step of treating a compound of the structural formula I: 
with sodium azide to form a triazole of formula II: 
wherein Rxe2x80x3 is C1-C6 alkyl and R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as previously defined.
In yet another embodiment, the present invention provides a method for preparing a compound of structural formula 1a: 
which includes the steps of
(a) treating an arylboronic acid of structural formula I: 
xe2x80x83with a compound of structural formula XI: 
xe2x80x83to form a compound of structural formula II: 
wherein X is halogen and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, and Y are as previously defined. In this embodiment, Y is preferably NR12.
Preferred R1 groups include hydrogen, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 haloalkyl. Most preferably, R1 is hydrogen.
Preferred R2 groups include NR10OR11, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, aryl, and heteroaryl groups are optionally substituted. More preferred R2 groups include C1-C6 alkyl, C1-C6 haloalkyl, and aryl. Most preferably R2 is optionally substituted C1-C6 alkyl, such as, for example, ethyl, iso-propyl, tert-butyl, and tert-amyl.
Preferred R3 groups include hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 haloalkyl. Most preferably, R3 is hydrogen.
Preferred R4 groups include NR10OR11, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, aryl, and heteroaryl groups are optionally substituted. More preferred R4 groups include C1-C6 alkyl, C1-C6 haloalkyl, and aryl. Most preferably R4 is NR10OR11 or optionally substituted C1-C6 alkyl, such as, for example, iso-propyl, tert-butyl, and tert-amyl.
Preferred R5 groups include hydrogen, F, Cl, Br, I, and optionally substituted C1-C4 alkyl. Also preferred are compounds of formulae 1 and 1a where R5is taken with R6 to form a five- to six-membered carbocyclic, a five- to six-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein the carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted. More preferably R5 is optionally substituted C1-C4 alkyl or is taken together with R6 to form a five- to six-membered carbocyclic, a five- to six-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein the carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted.
Preferred R6 groups include hydrogen, F, Cl, Br, I, and optionally substituted C1-C4 alkyl. More preferably, R6 is hydrogen or is taken together with R5 to form a five- to six-membered carbocyclic, a five- to six-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein the carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted.
Preferred R7 groups include C2-C5 alkyl and C2-C5 haloalkyl, wherein the alkyl, and haloalkyl groups are optionally substituted. More preferably R7 is optionally substituted C2-C5 haloalkyl.
Preferred R8 groups include hydrogen, F, C1-C6 alkyl, and C1-C6 haloalkyl, wherein the alkyl and haloalkyl groups are optionally substituted. More preferably R8 is hydrogen.
Preferred R9 groups include hydrogen and halogen. More preferably R9is hydrogen.
Preferred R10 groups include hydrogen and optionally substituted C1-C6 alkyl. Also preferred is R10 and R11 taken with nitrogen to form a five or six membered heterocyclic ring.
Preferred R11 groups include hydrogen and optionally substituted C1-C6 alkyl.
Preferred Y groups include NR12, O or S. More preferably Y is NR12.
Preferred R12 groups include hydrogen and optionally substituted C1-C6 alkyl.
In one preferred embodiment of the invention, R1 is selected from the group of hydrogen, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 haloalkyl; R3, R6, and R8 each independently is selected from the group of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 haloalkyl; R2 and R4 each independently is selected from the group of C1-C6 alkyl, C1-C6 haloalkyl, C5-C6 cycloalkyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted; R5 is optionally substituted C1-C6 alkyl; R7 is optionally substituted C2-C5 alkyl; and R9 is hydrogen or halogen.
In another preferred embodiment of the invention, R1 is selected from the group of hydrogen, optionally substituted C1-C3 alkyl, and optionally substituted C1-C3 haloalkyl; R3, R6, and R8 each independently is selected from the group of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 haloalkyl; R2 and R4 each independently is selected from the group of C1-C6 alkyl, C1-C6 haloalkyl, C5-C6 cycloalkyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted; R5 is optionally substituted C1-C6 alkyl; R7 is optionally substituted C2-C5 haloalkyl; and R9 is hydrogen or halogen.
In yet another preferred embodiment of the invention, R1, R3, R8 and R9 are hydrogen; R2 and R4 each independently is selected from the group of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted; R5 and R6 taken together form a five- to six-membered carbocyclic ring, a five- to six-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein said carbocyclic ring, heterocyclic ring, aryl and heteroaryl groups are optionally substituted; and R7 is optionally substituted C2-C5 alkyl.
In still another preferred embodiment of the invention, R1, R3, R8 and R9 are hydrogen; R2 and R4 each independently is selected from the group of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl and heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; R5 and R6 taken together form a five- to six-membered carbocyclic ring, a five- to six-membered heterocyclic ring, an aryl group or a heteroaryl group, wherein said carbocyclic ring, heterocyclic ring, aryl and heteroaryl groups are optionally substituted; and R7 is optionally substituted C2-C5 haloalkyl.
The compounds of formulae 1 and 1a represent a novel group of compounds RXR modulator compounds that have insulin sensitizing activity, but do not substantially suppress the thyroid axis and do not substantially elevate triglycerides. These compounds are heterodimer selective modulators of RXR activity. They bind to RXR with high affinity (Ki less than 20 nM) and produce potent activation of the RXR:PPARxcex3 heterodimer, but preferably do not activate the RXR:RAR heterodimer. This activation of PPARxcex3 in vitro is contemplated to be a major determinant of the antidiabetic efficacy of the compounds in vivo.
In a conventional cell-based co-transfection assay, the compounds of the invention act as partial agonists with respect to RXR homodimers and, together with PPAR modulators such as BRL, synergistically activate RXR:PPAR heterodimers. In contrast to their effect upon RXR:PPAR heterodimers, the compounds of the present invention do not significantly activate RXR:RAR heterodimers and in fact exhibit substantial RXR:RAR antagonist activity. In animal models of diabetes, such as the db/db mouse, the Sprague-Dawley rat and the ZDF rat, these compounds have been shown to regulate glucose and triglyceride levels. In contrast to previously characterized retinoids, these compounds are also contemplated to be non-teratogenic.
Applicants have discovered that one feature for achieving RXR modulator compounds with the desired activity is the length of the carbon chain at the R7 position. The preferred length of the carbon chain at this position is from 2 to 5 carbons. The most preferred or optimal length of the carbon chain within this range of 2 to 5 carbons will vary, depending upon the specific substitutions made at the other positions in Formula 1 or in Formula 1a. By varying the length of the carbon chain at the R7 position, the substituents at R2 and R4, and testing for desired activity, the preferred chain length for any specific compound within the scope of Formula 1 and 1a can be determined.
Table 1 shows a comparison of the activity of compounds of Formula 1 that are identical except for the length of the carbon chain at the R7 position or the presence of an oxygen linking the R7 substituent to the ring.
Table 2 shows an additional comparison of the activity of compounds of formulae 1 and 1a that have variations of the length of the carbon chain at the R7 position, variations of the substituents at R2 and R4 and ring systems incorporated at R5 and R6 taken together. Increased levels of triglycerides measured using the db/db mouse model were found not to correlate to increased triglyceride levels measured in the accepted Sprague-Dawley rat model. Data for Sprague-Dawley rats were included in Table 2 to indicate the profile of selected compounds of the invention in an accepted model for triglyceride measurements.
The rexinoids depicted above where R7 is less than 2 carbons in length and/or do not have an oxygen linking the R7 substituent to the ring (LG100268 and L1) are full RXR homodimer agonists. These compounds are efficacious insulin sensitizers in rodent models of Type II Diabetes, but they also raise triglycerides and suppress the thyroid hormone axis in these animals. On the other hand, a rexinoid such as L5, depicted above, where R7 is greater than 5 carbons is a full antagonist and has no effect on glucose, triglycerides or thyroid status in these same model systems. The activity of the compounds is dependent on the chain length of R7 and on the identity of R1, R2, R3, and R4, all of which can be substituted to affect the behavior of the rexinoid.
Those compounds that have a carbon chain length at the R7 position and appropriate substituents at R1, R2, R3, and R4 within the scope of the present invention maintain the desirable insulin sensitizing activity and eliminate or reduce both the suppression of the thyroid axis and triglyceride elevations (e.g., L3, L4, L6, L7). These compounds are heterodimer selective modulators of RXR activity. They bind to RXR with high affinity (Ki less than 20 nM) and produce potent activation of the RXR:PPARxcex3 heterodimer. Among these compounds, L3 and L4, having a chain length of 3 and 4 carbons, respectively, can be identified as the more preferred embodiments in this group based on the absence of detectable suppression of the thyroid hormone axis.
To minimize the undesirable increases in triglyceride levels and suppression of thyroid hormone axis, the modulators must not significantly activate the RXR:RAR heterodimer and must have substantial RXR:RAR antagonist activity. This requirement is clearly demonstrated by the two related compounds L2 and L3. The striking in vitro characteristic for these two compounds is that L3 has approximately twice the RXR:RAR antagonist activity as L2; this correlates with the distinction in vivo where L2 suppresses thyroid hormone axis while L3 does not.
When administered to obese, insulin resistant db/db mice (100 mg/kg by daily oral gavage for 14 days) these heterodimer selective RXR modulators lower both plasma glucose and triglyceride levels. However, unlike either full agonists (e.g., LG100268, L1) or partial agonists that exhibit less than 50% activity at the RXR:RAR heterodimer (e.g., L2), they do not substantially suppress total circulating levels of T4, or substantially increase triglyceride levels.
When administered to transgenic mice carrying the human apo A-I gene all of these compounds increase HDL cholesterol, but both LG100268 and L1 also raise triglycerides. Among the modulators that do not significantly activate the RAR:RXR heterodimer are those which do not raise triglyceride levels in the transgenic mouse model, consistent with their heterodimer selectivity. This effect is consistent with activation of PPARxcex1, and, in fact, in vivo these compounds synergize with the weak PPARxcex1 agonist fenofibrate.
The compounds of the present invention possess particular application as RXR modulators and in particular as dimer-selective RXR modulators including, but not limited to, RXR homodimer antagonists, and agonists, partial agonists and antagonists of RXRs in the context of a heterodimer.
In a second aspect, the present invention provides a method of modulating processes mediated by RXR homodimers and/or RXR heterodimers comprising administering to a patient an effective amount of a compound of the invention as set forth above. The compounds of the present invention also include all pharmaceutically acceptable salts, as well as esters and amides. As used in this disclosure, pharmaceutically acceptable salts include, but are not limited to: pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydoxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
The compounds of the present invention are useful in the modulation of transcriptional activity through RXR in the context of heterodimers other than RXR:RARxcex1,xcex2,xcex3 (e.g., RXR:.PPARxcex1,xcex2,xcex3; RXR:TR; RXR:VDR; RXR:NGFIB; RXR:NURR1; RXR:LXRxcex1,xcex2, RXR:DAX), including any other intracellular receptors (IRs) that form a heterodimer with RXR. For example, application of the compounds of the present invention to modulate a RXRxcex1:PPARxcex1 heterodimer is useful to modulate, i.e. increase, HDL cholesterol levels and reduce triglyceride levels. Yet, application of many of the same compounds of the present invention to a RXRxcex1:PPARxcex3 heterodimer modulates a distinct activity, i.e., modulation of adipocyte biology, including effects on the differentiation and apoptosis of adipocytes, which will have implications in the treatment and/or prevention of diabetes and obesity. In addition, use of the modulator compounds of the present invention with activators of the other heterodimer partner (e.g., fibrates for PPARxcex1 and thiazolidinediones for PPARxcex3) can lead to a synergistic enhancement of the desired response. Likewise, application of the modulator compounds of the present invention in the context of a RXRxcex1:VDR heterodimer will be useful to modulate skin related processes (e.g., photoaging, acne, psoriasis), malignant and pre-malignant conditions and programmed cell death (apoptosis). Further, it will be understood by those skilled in the art that the modulator compounds of the present invention will also prove useful in the modulation of other heteromer interactions that include RXR, e.g., trimers, tetramers and the like.
In the context of an RXR homodimer, the compounds of the present invention function as partial agonists. Further, when the modulator compounds of the present invention are combined with a corresponding modulator of the other heterodimeric partner, a surprising synergistic enhancement of the activation of the heterodimer pathway can occur. For example, with respect to a RXRxcex1:PPARxcex1 heterodimer, the combination of a compound of the present invention with clofibric acid or gemfibrozil unexpectedly leads to a greater than additive (i.e. synergistic) activation of PPARxcex1 responsive genes, which in turn is useful to modulate serum cholesterol and triglyceride levels and other conditions associated with lipid metabolism.
Whether acting on an RXR heterodimer pathway, or the RXR homodimer pathway, it will also be understood by those skilled in the art that the dimer-selective RXR modulator compounds of the present invention will prove useful in any therapy in which agonists, partial agonists and/or full antagonists of such pathways will find application. Importantly, because the compounds of the present invention can differentially activate RXR homodimers and RXR heterodimers, their effects will be tissue and/or cell type specific, depending upon the cellular context of the different tissue types in a given patient. For example, compounds of the present invention will exert an RXR antagonist effect in tissues where RXR homodimers prevail, and partial agonist or full agonist activity on the PPAR pathway where RXRxcex1:PPARxcex1 heterodimers prevail (e.g., in liver tissue). Thus, the compounds of the present invention will exert a differential effect in various tissues in an analogous fashion to the manner in which various classes of estrogens and antiestrogens (e.g., Estrogen, Tamoxifen, Raloxifen) exert differential effects in different tissue and/or cell types (e.g., bone, breast, uterus). See e.g., M. T. Tzukerman et al., Mol. Endo, 8:21-30 (1994); D. P. McDonnell et al., Mol. Endo., 9:659-669 (1995). However, in the present case, it is believed that the differential effects of the compounds of the present invention are based upon the particular dimer pair through which the compound acts, rather than through different transactiving regions of the estrogen receptor in the case of estrogens and antiestrogens. However, it is possible that they also function, in part, by tissue selectivity.
The particular conditions that may be treated with the compounds of the present invention include, but are not limited to, skin-related diseases, such as actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. With respect to the modulation of malignant and pre-malignant conditions, the compounds may also prove useful for the prevention and treatment of cancerous and pre-cancerous conditions, including, premalignant and malignant hyperproliferative diseases and cancers of epithelial origin such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposis sarcoma. In addition, the present compounds may be used as agents to treat and prevent various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA), metabolic diseases such as obesity and diabetes (i.e., non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus), the modulation of differentiation and proliferation disorders, as well as the prevention and treatment of neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Amyotrophic Lateral Sclerosis (ALS), and in the modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis.
The RXR modulator compounds, their pharmaceutically acceptable salts or hydrolyzable esters of the present invention may be combined with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian species, and more preferably, in humans. The particular carrier employed in these pharmaceutical compositions may vary depending upon the type of administration desired (e.g. intravenous, oral, topical, suppository, or parenteral).
In preparing the compositions in oral liquid dosage forms (e.g. suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g. powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be employed.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives can also be included. Furthermore, injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed.
For topical administration, the compounds of the present invention can be formulated using bland, moisturizing bases such as ointments or creams.
The pharmaceutical compositions and compounds of the present invention can generally be administered in the form of a dosage unit (e.g. tablet, capsule, etc.) in an amount from about 1 xcexcg/kg of body weight to about 1 g/kg of body weight, preferably from about 5 xcexcg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 xcexcg/kg of body weight to about 250 mg/kg of body weight, most preferably from about 20 xcexcg/kg of body weight to about 100 mg/kg of body weight. Those skilled in the art will recognize that the particular quantity of pharmaceutical composition and/or compounds of the present invention administered to an individual will depend upon a number of factors including, without limitation, the biological effect desired, the condition of the individual and the individual""s tolerance for the compound.
Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with modulators of the other heterodimeric partner with RXR (i.e., in combination with PPARxcex1 modulators, such as fibrates, in the treatment of cardiovascular disease, and in combination with PPARxcex3 modulators, such thiazolidinediones, in the treatment of diabetes, including non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus, and with agents used to treat obesity) and with other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
By utilizing the compounds of the present invention with modulators of the other heterodimeric partner one is able to utilize lower dosages of either or both modulators, thereby leading to a significant decrease in the side-effects associated with such modulators when employed alone at the strengths required to achieve the desired effect. Thus, the modulator compounds of the present invention, when utilized in combination therapies, provide an enhanced therapeutic index (i.e., significantly enhanced efficacy and/or decrease side-effect profiles) over utilization of the compounds by themselves.
Representative modulator compounds of the present invention include, without limitation those depicted below. 
The compounds of the present invention can be obtained by modification of the compounds disclosed herein or by a total synthesis approach using techniques known to those skilled in the art. In this regard, the synthesis of the dimer-specific RXR modulator compounds of the present invention follow established retinoid synthesis schemes and techniques as described in U.S. Pat. Nos. 4,326,055 and 4,578,498, the disclosures of which are herein incorporated by reference. See also, M. I. Dawson and W. H. Okamura, xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, Chapters 3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M. I. Dawson and P. D. Hobbs, The Synthetic Chemistry of Retinoids, In Chapter 2: xe2x80x9cThe Retinoids, Biology, Chemistry and Medicinexe2x80x9d, M. B. Sporn et al., eds. (2nd ed.), Raven Press, New York, N.Y., pp. 5-178 (1994); R. S. H. Liu and A. E. Asato, xe2x80x9cPhotochemistry and Synthesis of Stereoisomers of Vitamin A,xe2x80x9d Tetrahedron, 40:1931 (1984); Cancer Res., 43:5268 (1983); Eur. J. Med. Chem., 15:9 (1980); M. Boehm et al., J. Med. Chem., 37:2930 (1994); M. Boehm et al., J. Med. Chem., 38:3146 (1995); E. Allegretto et al., J. Biol. Chem., 270:23906 (1995); R. Bissonette et al., Mol. and Cellular Bio., 15:5576 (1995); R. Beard et al., J. Med. Chem., 38:2820 (1995); S. Canan-Koch et al., J. Med. Chem., 39:3229 (1996); WO 97/12853.
In addition to the synthetic techniques available in the prior art, the present invention further provides an improved method for making the claimed compounds, as well as structurally related RXR modulators, that efficiently and stereospecifically introduces the desired triene moiety with the correct olefin geometry. Scheme 1 describes a general method for producing RXR modulators of the present invention via a coumarin intermediate which is then ring opened to a diol and then further modified to the desired compounds. The new synthetic route is versatile, and can be adapted to the synthesis of an entire class of molecules with the appropriate variations.
The key sequence of reactions in this synthetic route involves utilizing an existing arylalcohol group as a functional handle to annulate a lactone ring on to the existing aromatic ring, forming a coumarin. The coumarin, by virtue of its cyclic structure, necessarily locks the olefin geometry as cis. The cis-geometry established in this step is then preserved throughout the remainder of the synthesis, yielding compounds of high isomeric purity without the need for isomerization of or discarding of the undesired isomers. Access to coumarin intermediates of the type required for construction of this important class of RXR modulators (e.g., Structure 4) can be achieved through either of two distinct strategies.
A coumarin such as 4 can be formed directly from an arylalcohol such as 2 through a von Pechmann or related cyclization reaction with a xcex2-keto ester such as 3. Alternately, the coumarin may be introduced from an ortho-hydroxyacetophenone such as 5 by condensation with a stabilized phosphorous ylide as shown in Structure 6. For further reference see, S. Sethna and R. Phadke, Organic Reactions, 7:1-58 (1953); H. J. Bestmann, et al., Angew. Chem. Int. Ed. Engl. 15(2):115-116 (1976).
After this cyclization step to form a coumarin such as 4, the lactone ring of the coumarin is then reductively opened to form a diol as shown in Structure 7. The diol then undergoes selective alkylation at the arylalcohol oxygen and mild oxidation of the allylic alcohol to the corresponding aldehyde (e.g., Structure 9). The synthesis is then completed by a standard Homer-Emmons/ester hydrolysis protocol. For further reference see, WO 97/12853, S. Canan-Koch et al., J. Med. Chem. 39:3229-34 (1996). 
Scheme 2 provides an example of the first method for producing a desired RXR modulator of the present invention. Beginning with a previously described tetramethyltetrahydronaphthol (e.g., Structure 2), a classical von Pechmann cyclization strategy using ethyl acetoacetate in 75% aqueous H2SO4 is used to regioselectively generate the 4-methylcoumarin ring system such as 4 in one step, setting the olefin geometry of the target compound. For further reference see, S. Canan-Koch et al., J. Med. Chem. 39: 3229-3234 (1996)); S. Sethna and R. Phadke, Organic Reactions, 7:1-58 (1953). Reductive ring opening of the lactone ring in 4 with LiAlH4 cleanly provides a diol such as 7. Selective alkylation of the phenol oxygen under extremely mild conditions is achieved using excess cesium fluoride and stoichiometric 1-iodopropane in DMF yields a primary allylic alcohol such as Structure 8. For further reference see, T. Sato and J. Otera, Syn. Lett., 336 (1995); J. H. Clark and J. M. Miller, Tetrahedron Lett., 18:599 (1977). Oxidation to an aldehyde such as 9 is accomplished with TPAP and NMO in CH2Cl2 (S. V. Ley et al., Synthesis, 639 (1994)). Horner-Wadsworth-Emmons olefination of 9 a with phosphonate such as 10 provides the remainder of the triene chain (See, B. E. Maryanoff and A. B. Reitz, Chem. Rev., 89:863 (1989)). Phosphonate 10 may be subjected to saponification with KOH in methanol to reveal the free acid target compound 1. 
Certain related molecules in this series of RXR modulators (e.g., See, WO 97/12853) that contain branched alkyl-substituted phenyl moieties in place of the tetramethyltetrahydronaphthyl group of 1 proved incompatible with the strongly acidic conditions employed in the von Pechmann cyclization step. Unwanted alkyl migrations occurred under these reaction conditions. Milder alternative routes to the coumarin intermediates were explored using the present substrate as a model. It was reasoned that construction of the lactone ring under neutral conditions would circumvent these undesired side reactions. Recently published routes to coumarins involving montmorillonite clays (e.g., See, T.-S. Li et al., J. Chem. Res., 38 (1998); G. K. Biswas et al, Indian J. Chem., 31B:628 (1992)) or Pd-catalyzed reaction of unsaturated esters (e.g., See B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 118:6305 (1996); M. Catellani et al., Tetrahedron Lett., 35:5923 (1994)) generally required highly electron-rich aryls for efficient Cxe2x80x94C bond formation to close the coumarin ring. Therefore, a potentially more generally applicable stabilized ylide approach was investigated. For further reference see, H. J. Bestmann et al., Angew. Chem. Int. Ed. Engl., 15(2):115 (1976).
As shown in Scheme 3, treatment of hydroxyacetophenone 5, which is prepared by acylation/Fries rearrangement of arylalcohol 2, with excess carbethoxymethylene-triphenylphosphorane in refluxing toluene cleanly produces coumarin 4. See, e.g., K. Fries and G. Fink, Ber., 41:4271 (1908); K. Fries and W. Pfaffendorf, Ber., 43:212 (1910); A. H. Blatt, Org. React., 1:342 (1942). This compound is identical in every respect to the compound obtained by the von Pechmann cyclization route. Given the ready availability of acetophenones and related precursors with varied alkyl substitution, this two-step approach to the key coumarin intermediate complements the von Pechmann cyclization method. 
LG100754, Compound 1 of Scheme 2, was synthesized in six steps in 61% overall yield from tetrahydronaphthol 2, with stereospecific introduction of the 6-cis-olefin through a coumarin intermediate. Employing the alternate synthetic route of Scheme 3, Compound 1 of Scheme 2 was prepared in seven steps, 66% overall yield via the stabilized ylide variation of Scheme 3. All of the reactions in this synthesis are amenable to multigram scale execution without significant loss of yield or stereochemical purity, and intermediates require minimal purification.
Scheme 4 describes a third method for preparation of the coumarin intermediates described by general Structure 4. The method involves conversion of a haloarylalcohol such as 11 to its corresponding arylboronic acid or arylboronate e.g., Structure 13 under Pd-catalysis in DMF. Subsequent Suzuki coupling of the resultant arylboronic acid or arylboronate with an ethyl cis-3-halocrotonate represented by Structure 15 produces coumarin intermediate 4. Concomitant cyclization to the corresponding coumarin ensues under the basic hydrolytic conditions employed for the Suzuki coupling chemistry (2 M K2CO3).
In a variant of the above described synthetic scheme, Suzuki coupling of the same ethyl cis-3-halocrotonate (15) fragment to a 2-alkoxyarylboronate 14 results in Z-ester 16. Alkoxyarylboranate 14 is prepared by alkylation of a 2-haloarylalcohol such as 11 to a 2-alkoxyaryhalide 12 prior to conversion to the arylboronic acid or arylboronate 14. Z-ester 16 may then be treated with LiAlH4 to intercept the coumarin based routes at the stage of allylic alcohol 